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Normocytic AnemiaSickle Cell nextOrgan Systems Hematology/Oncology Hematologic Disorders
10 questions
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339
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Definition of hemoglobinopathy: Hb structural abnormality that
causes hemolytic anemia
HbS: - globin gene point mutation substitutes valinefor glutamicacid at codon 6
less
At low O2tension, HbS polymerizes (the substituted Val
residue allows for hydrophobic interactions to occur between Hb
chains) RBCs sickle and cell membranes stiffen, becoming
more likely to hemolyze
Transportation of RBCs through inflamed tissue can also
lead to occlusion of microvasculature.
Inflammatory cells release mediators adhesion molecules
slowing of RBC passage through capillary beds sickling and
occlusion.
Sickled RBCs also obstruct microvasculature splenic
autoinfarction, painful crises
Confers malarial resistance in parts of Africa, 1/3 of
population carries HbS gene
Sickle cell disease: homozygousHbS, severe hemolytic anemialess
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Sickled shape is due to spontaneous polymerization of HbS
in deoxygenated state.
Painful crises during dehydration, infection, temperature
extremes, or sudden decreases in ambient O2tension (e.g. high
altitude)
Autosplenectomy increased risk of disseminated
infections from encapsulated bacteria (pneumococcus,
meningococcus, H. flu)
Viral infection (esp. parvovirus B19) aplastic crises with
major in hemoglobin concentration
Patients with sickle cell disease are at increased risk for
renal papillary necrosis andSalmonellaosteomyelitis Splenic sequestration occurs in children who have normal,
in tact spleens. Entrapment of sickled RBCs rapid
enlargement of the spleen. This can lead to hypovolemia and
shock and can be fatal.
Sickle cell patients may undergo extramedullary
hematopoeisis. Can often see the same characteristic "crew cut"
skull X-ray that occurs in other conditions with extramedullary
hematopoeisis (e.g., - thalassemia) Treatment: hydroxyurea (causes increased HbF synthesis,
used in severe cases)
Common Complications of Sickle Cell Anemia can be
summarized by the MNEMONIC :
Sickle cell anemia affects different AREASof the body:
Autosplenectomy, acute pain crisis
Renal papillary necrosis
Encapsulated organism infection (S. pneumo, Haemophilus, etc)
Aplastic anemia from Parvovirus B19
Salmonella osteomyelitis, Splenic sequestration
Sickle cell trait: heterozygous HbS, largely asymptomatic
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HbC: same codon is mutated as in HbS ( - chain, codon 6),
except lysine(not valine) is substituted for the glutamic acidless
HbC homozygotes have milder disease than HbS
homozygotes.
HbSC patients (heterozygous HbS and HbC) also have
milder disease vs. HbS homozygotes
Normocytic AnemiaAplastic Anemia nextOrgan Systems Hematology/Oncology Hematologic Disorders
3 questions
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339
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Toxin exposure hypocellular bone
marrow pancytopenia(including reticulocytopenia,
thrombocytopenia, and severe neutropenia)
Specific toxins that can produce aplastic anemia include:benzene, chloramphenicol, gold salts (old Tx for RA),
sulfonamides, phenytoin. It can also result from radiation and
chemotherapy.
Also in parvovirus infections (sickle cell patients at risk)
Labs: reticulocytopenia, normal MCV (in severe cases
macrocytosis, i.e., MCV > 100, may be seen).
Bone marrow aspiration shows hypocellularity.
If chronic and severe, hemosiderosis (systemic iron deposition)
can occur
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Microcytic AnemiaThalassemias nextOrgan Systems Hematology/Oncology Hematologic Disorders
37 questions
Top of Form
339
Bottom of Form
Thalassemias are anemias that are due to defects in synthesis
of - or - globinchains of hemoglobin.
less - Thalassemiais most prevalent in Asian and African
populations.
- Thalassemiais most prevalent in Mediterranean and
African populations.
Thalassemia carriers are protected againstPlasmodium
falciparummalaria.
Clinically significant thalassemias are inherited in
anautosomal recessivefashion.- Thalassemia results from deletionsof entire - globin genes.
less
There are 4copies of the - globin gene, two on each copy
of chromosome 16.
If 1 allele is deleted, the patient is asymptomatic.
If 2 alleles are deleted, this is known as - thalassemia trait.
The patient will develop a mild hypochromic anemia with
increased RBC count. This is not a clinically significant anemia.
Cis-deletions of 2 alleles are prevalent in Asian
populations.
Cis-deletions of 2 alleles increase the risk of hydrops fetalis
and severe - thalassemia in offspring.
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Trans-deletions of 2 alleles are prevalent in African
populations.
If 3 alleles are deleted, the patient will develop a severe
microcytic, hypochromic anemia.
If 3 alleles are deleted, - globin chains form
tetramers (HbH)which precipitate and damage RBCs. Note,
HbH is detectable by electrophoresis.
If 4 alleles are deleted,hydrops fetaliswill develop which
is lethal in-utero.
If 4 alleles are deleted, - globin chains form tetramers (Hb
Barts)which precipitate and damage RBCs. Note, Hb Barts is
detectable by electrophoresis.- thalassemiaresults from mutationsin - globin genes.
Common genetic mechanisms include point mutations or small
deletions within promoter regions or splice sites.less
There are 2 copies of the - globin gene, one on each copy
of chromosome 11.
Mutations can result in absent ( 0) production of - globin
chains. Mutations can also result in decreased(B+) production of -
globin chains.
- thalassemiaminorhas a genetic signature of / + , or
one normal allele and one under producing allele, leading to an
overall decrease in - globin.
- thalassemia minor ( / +) is the mildest form and is
usually asymptomatic.
Blood smear shows microcytic, hypochromic anemia with
increased RBC count and target cells.
Hb electrophoresis shows slightly decreased HbA with
increased HbA2 (>3.5%) and increased HbF.
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- thalassemia majorhas a gene signature of ( 0/ 0), meaning
that both - thalassemia alleles are non-functioning. As a result,
there is zero - globin production.less
- thalassemia major ( 0/ 0) presents with severe anemia
approximately 6 months after birth because the HbF (fetal
hemoglobin) does not require - globin.
In - thalassemia major, - globinchains form tetramers
which precipitate and damage RBCs. These damaged RBCs
then undergo extravascular hemolysis.
In - thalassemia major, ineffective erythropoiesis results in
extramedullary hematopoiesis in the liver, spleen, and otherbones (e.g. skull).
Extramedullary hematopoiesis in the liver and spleen
results in hepatosplenomegaly.
Extramedullary hematopoiesis in the skull results
in crewcutappearance on x-ray.
Extramedullary hematopoiesis in the facial bones results in
characteristic chipmunk facies.
Extramedullary hematopoiesis results in increasederythroid precursors leading to an increased risk of aplastic crisis
from parvovirus B19 infection.
Blood smear shows microcytic, hypochromic RBCs with
target cells and nucleated RBCs. Note, extramedullary
hematopoiesis results in nucleated RBCs.
Hb electrophoresis shows little or no HbA with increased
HbA2 and increased HbF.
Hypersplenism, from extramedullary hematopoiesis and
increased extravascular hemolysis, can result in splenic
infarction and abdominal pain. Note, the increased hemolysis
can also lead to bilirubin gallstones leading to RUQ pain.
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Hb electrophoresis is the diagnostic test of choice for
thalassemias.
Severe thalassemias generally require chronicblood
transfusions.less
Chronic blood transfusions increase the risk of secondary
hemochromatosis. Note, hemachromatosis can be treated with
iron chelation therapy using deferoxamine.
Overview of Anemia nextOrgan Systems Hematology/Oncology Hematologic Disorders
10 questions
Top of Form
339
Bottom of Form
MCV (mean corpuscular volume): One of the best lab values
used for categorizing anemias.
100 = macrocytic. 80-100 = normocyticMicrocytic Anemias: Thalassemias, Anemia of chronic
disease, Iron deficiency, Lead poisoning.
Can be remembered with mnemonic TAILless
Thalassemias will also show target cells, basophilic
stippling Sideroblastic anemia is associated with myelodysplastic
syndrome ("pre-leukemia") as well as chronic alcoholism and
lead poisoning.
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Anemia of Chronic disease commonly presents as
microcytic anemia
The best way to differentiate microcytic anemias is
by serum ferritin levels.
Thalassemia: Normal iron studies. (There is no deficiency of
iron.)
Anemia of Chronic disease: Ferritin, % saturation of
transferrin, serum iron.
Why?
- Inflammatory state (from chronic infection, immune disorders or
neoplasms) IL-6 production release of iron from iron
stores.
- Because iron stores are normal or elevated, ferritin
is increased.- However, circulating iron in the blood is low % saturation
of transferrin and serum iron.
Iron Deficiency Anemia: Ferritin because of deficient iron
stores.
TIBC can also be used to differentiate iron deficiency anemia
from anemia of chronic disease.
Recall that TIBC is inverselyproportional to the bodys iron
stores
- When iron stores are low(as in iron deficiency)
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TIBC is increased
- When iron stores are adequate (as in anemia of chronic
disease) TIBC isdecreased.
Macrocytic (megaloblastic) Anemias: B12and folate deficienciesless
B12(cobalamin) deficiency: associated neurologic defects
Folate deficiency: no neurologic defects
In both B12& folate deficiency, look for hypersegmented
neutrophils
Other lab findings:
- hyperhomocysteinemia (seen in both B12and folate deficiency)
- methylmalonylacidemia: seen in only B12deficiency
Drug induced (DNA synthesis inhibition): AZT, phenytoin
Normocytic Anemias pretty much everything else, but notable
examples:less
Anemia of chronic disease can also cause a normocytic
anemia. Leukemias and aplastic anemia
Enzyme defects (G6PD deficiency)
Hemoglobinopathies (HbC, sickle cell), look for target cells
Haptoglobin: binds free serum hemoglobinless
serum haptoglobin suggests intravascular hemolysis
(more Hb released into serum)
haptoglobin can suggest liver disease (liver cannot
produce normal levels of haptoglobin)
LDH (lactate dehydrogenase): abundant in RBCsless
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serum LDH can suggest hemolysis, but this is
nonspecific (need more evidence for hemolysis to make the
diagnosis)
Direct Coombs Testless
The direct Coombs test (aka direct antiglobulin test) is used
to detect antibodies that are bound directlyto the surface of
RBCs.
RBCs are exposed to anti-humanglobulin. If anti-
RBC antibodies are present on the surface of RBCs, the anti-
human globulin will cause agglutination, thus constituting a
positive test. A positive Direct Coombs Test suggests autoimmune
hemolysis.
Indirect Coombs Test: detects free-floating antibodiesin serumless
A serumsample is incubated with RBCs with known
antigens
RBC agglutination = positive Indirect Coombs Test
Used to cross-match blood for transfusion and in antenatalantibody screening (anti-Rh antibodies against a RH+fetus)
Megaloblastic Anemias nextOrgan Systems Hematology/Oncology Hematologic Disorders
8 questions
Top of Form339
Bottom of Form
B12/folate deficiency DNA synthesis RBCs grow larger
than normal before dividing
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A Quick Review of B12/Folate Metabolism:
*Folate is absorbed in the jejunum. The enzyme intestinal
conjugase(which is inhibited by phenytoin) is required for
absorption.
*Vitamin B12 is absorbed in the terminal ileum. B12 absorption is
slightly more complicated:
-B12 is bound by R-factor which protects it from gastric acidity
-In the duodenum, pancreatic enzymes hydrolyze the R-factor
bond and B12 is bound by IF (which is synthesized by gastric
parietal cells).
-The B12-IF complex is absorbed in the terminal ileum.
*Folate and B12 are required for the synthesis of dTMP.
B12 deficiency causes neurological symptoms:
-Loss of dorsal column function ( vibration and position sense)
-Loss spinocerebellar tracts proprioception
-Demyelination of the lateral corticospinal tract spasticity,
weakness
Neurological symptoms are due to failure of Methylmalonyl CoA
Succinyl CoA.
Methylmalonyl CoA causes an Propionyl CoA (the
precursor) replacement of acetyl CoA with Propionyl CoA
demyelination.
Note: Megaloblastic anemia caused by B12 deficiency canbe corrected by folate administration, but the neurological
symptoms can not!
Laboratory Findings:
-Hypersegmented neutrophils
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- serum homocysteine (B12 deficiency and Folate deficiency)
and serum methylmalonic acid (B12 only)
Pernicious anemia: autoimmune gastritis leading to IF
(intrinsic factor)less
Also look for achlorhydria, antibodies against IF
(pathognomonic) and parietal cells, pancytopenia,
hypersegmented neutrophils
Schilling Test, part 1:
- patient is given an oral dose of radiolabeled B 12followed by an
intramuscular injection of nonradiolabeled B12
- positiveif < 5% of the radiolabeled B12is detected in urine after
24 hours (indicates pernicious anemia or malabsorption)
Schilling Test, part 2 (perform if part 1 is positive):
- give oral IF+ labeled B12, followed by IM injection of nonlabeled
B12.
- If urine B12 then its pernicious anemia. If urine B12doesnt ,its malabsorption (e.g. Crohns disease, the fish
tapeworm Diphyllobothrium latum)
Explanation of Schilling Test:
The Schilling test is done when a GI cause for B12 deficiency is
suspected. Under normalcircumstances, radioactive B12 should
be absorbed in the gut and excreted in the urine. When there is a
defect in the absorption pathway, lessB12 is seen in the urine.
At that point, the potential causes of B12 malabsorption can be
individually ruled out. What are the causes of B12
malabsorption?
-Pernicious Anemia IF deficiency
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-Bacterial overgrowth B12 breakdown
-Pancreatic insufficiency absorption
-Intestinal tapeworm (diphyllobothrium)
-Terminal ileal disease inability to absorb B12
By replacing missing enzymes (IF or pancreatic) or giving
antibiotics (for bacterial overgrowth) the urine can be analyzed
for an increasein the amount of B12 signifying that B12 has
been absorbed normally.
Folate deficiency: Similar to B12 deficiency in presentation,
except there are NO neurological symptoms.less
Commonly seen in :-Alcoholics
-Pregnancy
-Celiac sprue
-Giardiasis
-Phenytoin use
-Chemotherapeutic agents (e.g. methotrexate)
-TMP-SMX (TMP is a dihydrofolate reductase inhibitor)
-Valproic acid (folate deficiency causes neural tube defects)-Zidovudine
Normocytic AnemiaEnzyme
eficiency nextOrgan Systems Hematology/Oncology Hematologic Disorders
6 questionsTop of Form
339
Bottom of Form
G6PD: X-linked recessive
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less
G6PD deficiency NADPH formation via the Hexose-
Monophosphate Shunt.
NADPH is responsible for regenerating the reduced form of
glutathione from its oxidized form. Glutathione fights oxidative
stress in the cell.
Without NADPH, Glutathione is not regenerated the cell is
more vulnerable to oxidative stress hemolysis
10% incidence in African Americans and persons of
Mediterranean heritage
Exposure to oxidative stress acute, self-limited
intravascular hemolysis hemoglobinuria (dark urine),
hemoglobinemia and jaundice
Oxidative stressors: infection, primaquine, sulfas, nitros,
fava beans
Heinz Bodies:intracytoplasmic aggregates of precipitated
hemoglobin.
Bite Cell:Splenic macrophage will attempt to phagocytose theHeinz body formation of bite cells.
Pyruvate Kinase deficiency: autosomal recessiveless
Chronic lack of ATP leads to membrane damage
extravascular hemolysis.
Pyruvate kinase is an ATP-producing enzyme in the
glycolytic pathway. Since RBCs can only
produce ATP viaglycolysis, this deficiency severely effects theability of RBCs to produce energy. Decreased ATP production in
the RBC altered membrane integrity hemolysis
!olycythemia
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nextOrgan Systems Hematology/Oncology Hematologic Disorders
13 questions
Top of Form339
Bottom of Form
Polycythemia: Hct, Hb, and RBC count.
Absolute polycythemia: total RBC mass.
Appropriate polycythemia: RBC count increase in response to
chronic hypoxia.
less Hypoxic stimuli O2saturation due to:
- High altitude
- Primary lung disease
- Cyanosis (due to heart disease or CO exposure)
RBC count, RBC mass, and EPO.
Plasma volume (PV)= normal.
Inappropriate polycythemia: RBC count increase withouthypoxic stimulus.
less
No hypoxic stimuli normal O2saturation.
Ectopic EPO production (e.g. from RCC)
RBC production RBC mass and RBCcount
The normal O2saturation distinguishes inappropriate from
appropriate polycythemia.
Plasma volume (PV) can be normal orincreased.
Inappropriate absolute polycythemia from
ectopic EPO production normal PV.
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Inappropriate absolute polycythemia from polycythemia vera
increased PV.
Relative polycythemia: Decreased plasma volume increased
Hct, Hb, and RBC countrelativeto total plasma volume.less
Due to volume depletion:
- Sweating
- Diarrhea
- Burns
Corrected by fluid replacement add whatever was lost.
Usually due to sweating hyposomotic fluid loss replace with
hypotonic salt solution (i.e. Gatorade or Powerade).
Summary of lab findings in polycythemialess
Polycythemia SaO2 RBC Mass PV EPO
Relative polycythemia Normal Normal Normal
Appropriate polycythemia Normal
Inappropriate polycythemia Normal Normal
P. vera Normal
Polycythemia vera: Due to acquired mutations to myeloid stem
cells.
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Microcytic AnemiaAnemia of
Chronic isease nextOrgan Systems Hematology/Oncology Hematologic Disorders
6 questions
Top of Form
339
Bottom of Form
Anemia of chronic disease occurs in the setting of a chronicinfectious or inflammatory process. It is one of the most
common causes of anemia in hospitalized patients.less
Common causes include :
- Chronic infectious processes (TB, osteomyelitis, lung abscess)
- Malignancy (breast, lung, Hodgkins lymphoma)
- Autoimmune disease (SLE, RA)
Pathophysiology of anemia of chronic disease is related to thepersistent release of inflammatory mediators.
less
Inflammatory state IL-6 production release of iron
from iron stores by upregulating synthesis of hepcidin.
Hepcidin is a hepatic protein which inhibits transport of
ironfrom bone marrow macrophages to developing RBCs. Thus, RBCs production takes place in a state of perceived
iron deficiency (despite the fact that iron stores are in fact
adequate).
Laboratory examination is crucial for differentiating anemia of
chronic disease from iron deficiency anemia.
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less
Because iron stores are normal or elevated, ferritin
is increased.
However, circulating iron in the blood is low % saturation of
transferrin and serum iron.
RBCs are generally microcytic and hypochromic, however
they can also be normocytic and normochromic.
Summary of Labs in Anemia of Chronic Disease :
- Ferritin
- MCV
- Serum Iron
- % Saturation of Transferrin
- TIBC
Comparison of Labs in Anemia of Chronic Disease and Iron
Deficiency Anemia:
"ron eficiency Anemia of Chronic isease Ferritin Ferritin
MCV MCV
% Sat % Sat
TIBC TIBC
Treatment of underlying inflammatory condition is paramount.
Do NOTgive iron!
Microcytic Anemia"ron eficiency nextOrgan Systems Hematology/Oncology Hematologic Disorders
9 questions
Top of Form
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339
Bottom of Form
Iron deficiency anemia is most commonly the result of chronic
blood loss: menorrhagia, gastrointestinal bleeding (e.g. colonicpolyp or cancer, Meckels diverticulum in children).
less
Can also occur in breast fed infants; human milk has low
iron.
Also, note that iron is absorbed in the duodenum, so any
disease process of the small bowel (i.e. Crohns, celiac) thataffects the duodenum may compromise iron absorption.
Plummer-Vinson Syndrome: Triad of anemia, glossitis and
esophageal webs. Be suspicious if a patient presents with
symptoms of dysphagia and has concurrent anemia.less
Patients with Plummer Vinson syndrome may have
increased risk of developing esophageal squamous cell cancer.
Labs: serum iron, ferritin, and TIBCless
Ferritin is the intracellular protein that stores iron.
Serum ferritin is correlated to intracellular iron stores
serves as an excellent way to differentiate iron deficiency anemia
( ferritin) from anemia of chronic disease ( ferritin)
The increase of TIBC is due to a decrease in the total
number of binding sites occupied by iron. Rememberthat TIBC and Transferrin always change in the same direction!
The change in transferrin is due to a negative feedback process.
When the body senses a decrease in total iron upregulation of
Tf synthesis
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MCV (microcytic)
Iron deficiency anemia is treated by replenishing iron stores.less
Oral Iron :
- Oral iron is the mainstay therapy for iron deficiency anemia.
- Oral iron tablets should not be taken with tea, coffee or calcium
supplements as these will decreasethe absorption.
- Conversely, acidity (Vitamin C or orange juice) will increasethe
absorption of iron.
- Side effects of oral iron include: nausea, vomiting and
constipation. Additionally, iron tablets will cause the stool to
appear black, but this is NOT because of GI bleeding.
Parenteral Iron :
- IV iron is used in patients who are unable to absorb iron
enterally (small bowel resection, inflammatory bowel disease,
etc.)
- It must be administered in the hospital.- Generally well tolerated, however one formulation, iron dextran,
can cause life-threatening anaphylaxis.
Blood Transfusion :
- Blood products are generally reserved for patients who are
unstable (either hypotensive due to bleeding or hypoxic due to
anemia).
- The threshold for transfusion varies based on the patients co-
morbid conditions, but is generally considered to be hemoglobinof 7 for healthy patients and hemoglobin of 10 for patients
with CAD.
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Normocytic Anemia#emolytic
Anemias nextOrgan Systems Hematology/Oncology Hematologic Disorders
9 questions
Top of Form
339
Bottom of Form
Warm autoimmune hemolytic anemia: positive Direct CoombsTestless
Most common immune hemolytic anemia
IgGautoantibodies (most active at 37C, hence "warm")
Associated with underlying diseases: SLE, Hodgkin/non-
Hodgkin lymphomas, chronic lymphocytic leukemia
Associated with some drugs, e.g., - methyldopa
stimulates production of autoantibodies against Rh antigens Commonly results in extravascular hemolysisby splenic
macrophages splenomegaly
Cold agglutinin disease: RBCs clump when placed on ice but
disaggregate when re-warmedless
IgMantibodies, usually against I group antigen
Can be triggered by EBV or Mycoplasma
pneumoniaeinfections
"The 3 Ms" mnemonic: IgM, Mycoplasma, Mononucleosis
Mnemonic for remembering cold vs warm
agglutination: Georgia is warmer than Maine.
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CD59 attachment. The corresponding gene
is PIGA(phosphatidylinositol glycan class A), on the X
chromosome.less
CD55 and CD59 inactivate complement. The GPI anchor
deficiency leads to complement mediated hemolysis.
Patients occasionally (paroxysmally) wake up with
hemoglobinuria (nocturnal)
Sxs: anemia, thrombosis, pancytopenia, hypercoagulable
state
#o$gkin%s &ymphoma nextOrgan Systems Hematology/Oncology Hematologic Malignancies
10 questions
Top of Form
339
Bottom of Form
Malignancy that usually affects young malesless
All subtypes of Hodgkins lymphoma are more common in
males except nodular sclerosingtype, which affects young
women greater than men.
The identification of Reed-Sternberg (RS) cells is requiredfor
diagnosis of Hodgkin lymphoma.less
RS cells are classically seen as a cell with 2 nucleisurrounded by clear cytoplasm.
Reed-Sternberg cells are of B cell origin and are CD15 and
CD30 positive
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less
Associated with EBV infection in approximately 40% of
cases good prognosis
Lymphocyte-depleted: Least common form (
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B cells that have undergone somatic hypermutationto become
plasma cells.
Malignant cells readily seen on bone marrow
biopsy/aspiration, which is requiredfor diagnosis.
MM is generally considered a disease of the elderly, with peak
incidence occurring between ages 65-70.less
Common features can be remembered with mnemonic :
MM patients can be crabby CRABBI
HyperCalcemia
Renal insufficiency
AnemiaBence-Jones proteinuria
Bone lesions (lytic)
Infections
Because immunoglobulin production is compromised, the
most common cause of death isrecurrent infection.
Bence Jones proteinuria: Ig light chains in urine.
This causes renal insufficiency 2nd most common cause of
death.
Peripheral smear: rouleaux, a stacking of RBCs which is a
sign of inflammation.
Amyloidosis(AL type) often occurs because of the
excessive production of light chains.
Tumors produce lytic lesionsof bone severe bone pain,
spontaneous fracturesless
Skull & axial skeleton most commonly involved
Excessive bone resorption can precipitate hypercalcemia,
which can present with neurological manifestations such as
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confusion and weakness, as well as polyuria, constipation and
bone pain (recall: bones, stones, groans and psychic
overtones).
Since a plasma cell can only produce 1 antibody and this is a
clonal population massive quantities of one immunoglobulin
M protein. NOTE: This is not the same M-protein associated
with strep pyogenes!less
Single, sharp spike on electrophoresis
Usually IgG or IgA
Normal antibody synthesis can be impaired infection
(e.g. pneumococcus, Hemophilus)MGUS(monoclonal gammopathy of undetermined significance
(5-10% of healthy older persons)less
Monoclonal M protein spike w/o Bence Jones proteinuria
Asymptomatic, benign
No concentration of normal immunoglobulins
Waldenstrm macroglobulinemia: neoplastic B cells
in lymphoplasmacytic lymphomaproduce monoclonal IgMless
No bony lesions
Waldenstrm macroglobulinemia is most commonly
characterized by a hyperviscosity syndrome.
1) Neurologic symptoms: Visual impairment, headaches, deafness,
lethargy.
2) Cryoglobulinemia: Precipitation of macroglobulins at low
temperatures (may require plasmapheresis).
3) Bleeding: Consumption of clotting factors into large complexes with
macroglobulins can interfere with the coagulation cascade.
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Approximately 10% of patients have autoimmune hemolytic
anemia caused by IgM (cold agglutinins).
Non(#o$gkin &ymphomaOverview nextOrgan Systems Hematology/Oncology Hematologic Malignancies
4 questions
Top of Form
339
Bottom of Form
Non-Hodgkins Lymphoma (NHL) is a malignant neoplasm, oftenoriginating from lymph nodes/lymphoid tissues
less
B-cell Lymphoma: originate from B-cells within the
germinal follicle and include:
-Burkitts Lymphoma
-Diffuse large B-cell lymphoma (DLBCL)
-Follicular lymphoma
-Small lymphocytic lymphoma (SLL)-MALToma
T-cell lymphoma:
-Mycosis fungoides and Sezary syndrome
Periaortic nodes often involved
Noncontiguous spread observed
There are several infections and predisposing conditions
associated with the pathogenesis ofNHL
less
Bacterial Infections
-H. pylori: MALToma a low grade lymphoma found in the
gastric mucosa-associated lymphoid tissue (i.e. MALT)
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Viral Infections
-HTLV-1 (Human T-cell leukemia virus type I): adult T-cell
lymphoma
-EBV: Burkitts lymphoma, DLBCL, CNS lymphoma
-HCV: B-cell lymphoma
Hashimotos thyroiditis predisposes to thyroid lymphoma
Diffuse large cell lymphoma (DLBCL): most common non-
Hodgkins lymphoma. 80% are B-cell in origin, remaining 20%
are T-cell in origin.less
Presentation: Typically presents as rapidly enlarging mass
that can present anywhere in the body. Can be found in nodalor extranodal tissue. Associated with an aggressive, widespread
dissemination rapidly fatal if untreated.
CD19+ and CD20+
Non(#o$gkin &ymphoma)'rkitt
&ymphoma nextOrgan Systems Hematology/Oncology Hematologic Malignancies
3 questions
Top of Form
339
Bottom of Form
Burkitt's lymphoma is linked to EBV infection
less
Burkitts lymphoma (small non-cleaved non-Hodgkin's
lymphoma): B-cell lymphoma
-African form: maxilla/mandible involvement
-American form: abdominal organ involvement
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"8urkitt's" (8 looks like a B):
t(8;14) translocation c-mycproto-oncogene moved next to Ig
heavy chain gene c-myc overexpression cell proliferation
(high grade)
Can also be caused by t(2;8) or t(8;22)
Starry sky appearance: normal macrophages ingest cellular
debris from rapid cell turnover
Because Burkitt lymphoma exhibits a very high mitotic rate
and rapid turnover of cells with high levels of apoptosis, it
inherently can NOT express Bcl-2. Contrast this with follicular
lymphoma where translocation causes overexpression of Bcl-2.
Non(#o$gkin &ymphomaT(Cell
&ymphoma nextOrgan Systems Hematology/Oncology Hematologic Malignancies
4 questions
Top of Form
339
Bottom of Form
Precursor T-cell lymphoblastic leukemia/lymphoma commonly
presents with a mediastinal mass.less
Formerly "lymphoblastic lymphoma", but the WHO now
classifies it as a form of ALL Thymic lymphocyte origin
Usually occurs in children
Rapid progression (b/c its an ALL variant)
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Mycosis fungoides and Sezary syndrome are neoplastic
conditions of CD4+ Helper T cellsless
Mycosis Fungoidespresents as a cutaneous rash which
spreads to lymphoid tissue, liver and lungs.
Sezary Syndromeoccurs when CD4+ T cells invade the
blood leukemia. The circulating cells are called Sezary cells
Non(#o$gkin &ymphomaSmall
&ymphocytic &ymphoma
nextOrgan Systems Hematology/Oncology Hematologic Malignancies
17 questions
Top of Form
339
Bottom of Form
Small lymphocytic lymphoma (SLL) is a neoplasm of mature
(peripheral), small, monoclonal B-cells.less
SLL is considered the same disease as chronic
lymphocytic leukemia (per WHO) but SLLis limited to lymph node
involvement.
Men, older than 60 years of age are most commonly
affected.
SLL is preceded by monoclonal B-cell lymphocytosis, which
results from cytogenetic abnormalities leading to an abnormal
response to antigen stimulation and thus proliferation of the
mutated B-cell.less
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Affected B-cells express mutated B-cell receptors, which
allow antigen-independent, autonomous signalling promoting cell
survival.
The diagnosis of SLL relies on excisional lymph node biopsy
along with analysis of a bone marrow biopsy and aspirate.less
SLL most commonly runs an indolent course, and patients
are often asymptomatic.
Physical exam can show generalized painless
lymphadenopathy, and hepatosplenomegaly.
Coombs test will show warm antibody hemolytic anemia
(IgG mediated). CBC will show mild lymphocytosis. And flowcytometry shows B-cells expressing CD19/20/23 and 5 (normally
a T-cell marker).
Nodal biopsy will show nodal architecture effacement, small
lymphocytes, and some larger lymphoid cells arranged
in pseudo follicles (pathognomonic).
Genetic abnormalities are most commonly of chromosomes
11, 12, or 13.
SLL monoclonal B-cell proliferation leads to defects of thecellular and humoral immune systems.
less
Patients are at increased risk of infection by encapsulated
bacteria (Streptococcus pneumoniae, Staphylococcus
aureus, Haemophilus influenzae), and reactivation of latent
Herpesvirus infections.
Patients may also have an increased risk for: anemia,
thrombocytopenia, other cancers (hematologic and solid tumor),
leukostasis, and tumor lysis syndrome.
Treatment of early, asymptomatic SLL is observation.less
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show neutropenia or thrombocytopenia. Pancytopenia is present
in up to 50% of patients at time of diagnosis.
The blood smear in myelodysplastic syndrome will show
dysplastic red and white cells. Ovalomacrocytosis is the best-
recognized abnormality of the red cells, and neutrophils may
have increased size, abnormal lobation, and abnormal
granularity. Ringed sideroblasts, basophilic stippling, Howell-Jolly
bodies, or megaloblastoid nucleated RBCs may also be seen.
Bone marrow aspirate/biopsy in myelodysplastic syndrome
may show increased myeloid precursors (though, by definition,
less than 20% blasts) and dysplastic features. Bone marrow is
usually hypercellular; this, combined with peripheralpancytopenia, indicates high rates of intramedullary cell death.
Many patients are asymptomatic and myelodysplastic
syndrome is found incidentally on routine CBC.
Physical exam findings are nonspecific and include pale
complexion, petechiae/purpura, recurrent infections, bruising, or
abnormal bleeding. Sweet syndrome (neutrophilic dermatosis)
may also be seen.
Complications of myelodysplastic syndromes are due to theabnormalities in blood and bone marrow cell morphology and
number.less
These complications (of myelodysplastic syndrome) include
anemia (RBC), bleeding/bruising/petechiae/purpura
(thrombocytopenia), and recurrent infections (neutropenia).
Myelodysplastic syndrome can progress to acute myeloid
leukemia (AML), which is diagnosed when blast counts rise
above 20%, or if myeloid sarcoma (solid tumor composed of
myeloblasts) is present.
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Blood smear for a patient with myelofibrosis may show
poikilocytosis (red-blood cells (RBCs) with different shapes),
anisocytosis (RBCs of different sizes), nucleated RBCs,
polychromasia, and teardrop shaped RBCs.
Bone marrow aspirate from a patient with myelofibrosis
may show a dry tap. It may also show neutrophilic and
megakaryocytic hyperplasia.
Bone marrow biopsy is essential for appreciation of the
marrow fibrosis seen in almost all patients with myelofibrosis.
A hallmark finding in the bone marrow of myelofibrosis
patients is hypervascularity, believed to be caused by the
increased amount of secreted endothelial growth factor. MRI Imaging of a patient with myelofibrosis will show
changes in the bone marrow from fatty to fibrotic.
In myelofibrosis, the increased numbers of megakaryocytes
secrete increased amounts of cytokines and growth factors,
which leads to activation of fibroblasts and fibrosis of bone
marrow.less
Once the bone marrow becomes fibroticinmyelofibrosis, hematopoiesis becomes extramedullary. This can
be seen in any body tissue; soft tissue, body cavities, serosal
surfaces, CNS, skin, etc, and is picked up on CT scan or MRI.
Myelofibrosis can progress to acute leukemia.
Treatment for myelofibrosis is mostly supportive, directed at
correcting abnormal blood cell counts.less
Allogeneic hematopoietic cell transplantation is the only
treatment with curative potential.
Myelofibrosis patients may also receive pharmacologic
therapy including chemotherapy, hydroxyurea (for
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thrombocytosis), JAK2 inhibitors, interferon alpha, androgens, or
thalidomide.
Splenectomy is often performed for patients with
myelofibrosis.
!olycythemia *era nextOrgan Systems Hematology/Oncology Hematologic Malignancies
16 questions
Top of Form
339
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Polycythemia vera: Absolute polycythemia without hypoxic
stimulus, usually due to mutation on JAK2 gene of chromosome
9.less
Clonal expansion of myeloid stem cell.
Same mutation found in myelofibrosis, myeloid metaplasia,
and essential thrombocythemia. Increased production of:
- RBCs
- Granulocytes
- Mast cells
- Platelets
Symptoms due to hyperviscosityand vessel congestion.less
Hepatosplenomegaly: Engorgement with blood cells.
Burning pain in the hands due to micro thrombi occlusion of
vessels. Also seen in essential thrombocythemia.
Ruddy face (plethoric): Due to vessel congestion.
Thrombosis: Due to hyperviscosity.
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CNS involvement: Due to hyperviscosity.
- Headache
- Blurred vision
- Retinal vein engorgement
- Vertigo
- Transient ischemic attack
- Stroke
Increased histamine: Peptic ulcers and itching after
bathing.
Gout: Due to increased cell turnover with release of nucleic
acids.
Decreased erythropoietin (EPO) with increased hematopoiesisless
EPO and normal O2sats (>92%).
RBC mass, RBC count, and plasma volume.
May see leukocytosis, thrombocytosis.
Leukocyte alkaline phosphatase > 100.
B12> 900 pg/mL or B12binding protein.
Treatment used to reduce red blood cell proliferation
(chemotherapy), reduce hematocrit (phlebotomy), and prevent
thrombosis (aspirin).less
Perform phlebotomy, hydroxyurea, or aspirin.
Thrombotic complications are a major cause of morbidity
and mortality
&e'kemias nextOrgan Systems Hematology/Oncology Hematologic Malignancies
18 questions
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339
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Bottom of Form
Leukemic cells often infiltrate the marrow, disrupting normal
hematopoiesis:less
Leukopenia infection risk Anemia
Thrombocytopenia hemorrhagic complications
Acute leukemiasless
Clinical findings generally abrupt in onset.
Fever, bleeding and fatigue are commonly found.
Laboratory findings-Thrombocytopenia
-Hypercellular bone marrow with >20% blasts
-Usually an elevated WBC count
Acute leukemias have a bimodal distribution, and occur in
children and adults >60 years of age.
The acute leukemias are often tatal within 6 to 12 months if
there is no intervention.
ALL (Acute lymphoblasticleukemia)less
Most common malignancy in children, also the most
responsive to therapy
There are 2 general types: B-ALL and T-ALL
B- ALL :
-Presents as blood disorder, will generally metastasize to CNS
-Surface Markers: CD10 (aka CALLA), CD19, CD20 and CD22-Translocation: t(12;21) is commonly asked
T- ALL:
-Presents commonly as anterior mediastinal mass
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2 questions
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339
Bottom of Form
mant11e:
t(11;14)translocation bcl-1 (cyclin D1) overexpression
cell cycle high grade; terrible prognosis with average survival
of 3 yearsless
Mantle cell (zone) lymphoma: B-cellsform the mantle zone
of lymphoid follicles Morphology is similar to SLL/CLL (SLL is considered a
phase of CLL)
Mantle cell NHL vs. CLL (chronic lymphocytic leukemia):
- both express CD5, CD19, CD20
- Mantle cell NHL is CD23-vs. CLL is CD23+
Incurable. Often aggressive, disseminated, affects older
men
Non(#o$gkin &ymphoma+ollic'lar
&ymphoma nextOrgan Systems Hematology/Oncology Hematologic Malignancies
3 questions
Top of Form
339
Bottom of Form
Follicular Fourteen:
t(14;18)translocation juxtaposition of bcl-2(an oncogene that
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inhibits apoptosis) next to the IgH locus. This leads
to overexpression of BCL2 apoptosis.less
Follicular lymphoma: B-celllymphoma, second most
common non-Hodgkin lymphoma
Classically presents in adults with waxing and waning
lymphadenopathy
Predominantly centrocytes (small cleaved cells)
expressing:
- CD10+, CD19+, CD20+
- BCL2+, BCL6+
Lymph nodes are obliterated by characteristic neoplasticnodules: uniform, round, and isolated. These nodules are
comprised of B-cells recapitulating the germinal centers of
lymphoid follicles
#ematopoiesis nextOrgan Systems Hematology/Oncology Hematopoiesis
10 questions
Top of Form
339
Bottom of Form
Primary lines: myeloid vs. lymphoid
During hematopoeisis, cytokines and growth factors direct
commitment of progenitor cells into and through specific
lineages.
Platelet productionless
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Production of megakaryocytes and platelets is primarily
regulated by thrombopoietin, a glycoprotein hormone produced
by the liver and kidneys.
IL-6 stimulates the assembly of platelets from
megakaryocytes.
Erythropoiesisless
Controlled by erythropoietin(EPO), a glycoprotein
hormone produced in kidneys and liver.
Mast cell productionless
Primarily regulated by Stem Cell Factor (SCF, aka c-Kitligand)
Cofactors: IL-3, IL-6, thrombopoietin, nerve growth factor
Granulopoiesisless
Basophils:
- granulocyte-macrophage colony-stimulating factor (GM-CSF):
basophil growth and differentiation, mast cell differentiation
- IL-3
- TGF- (suppresses eosinophil lineage, stimulates production of
basophils)
Neutrophils:
- GM-CSF
- granulocyte colony-stimulating factor (G-CSF)
Eosinophils:
- GM-CSF
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nextOrgan Systems Hematology/Oncology Hematopoiesis
3 questions
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Bottom of Form
Biconcave to maximize surface area for gas exchange
Lack organelles: no nuclei, no mitochondria
Glucose is the sole fuel (glycolysis only)less
Also uses glucose for NADPH via HMP shunt to preventoxidative damage
Average survival: 120 daysevery 120 days, the
entire RBC population is replaced
,ran'locytes nextOrgan Systems Hematology/Oncology Hematopoiesis
9 questions
Top of Form
339
Bottom of Form
Subclass of leukocytes; includes: basophils, neutrophils, and
eosinophils
Basophil granules contain:
less
Bilobed nucleus. Intracellular granules stain well with basic
dyes, hence "basophilic"
Heparin
Histamine key role in mediating allergic reactions
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Leukotrienes and cytokines are synthesized on demand
Neutrophil granules contain myeloperoxidase, lactoferrin,
hydrolytic enzymesless
Most common WBC, highly motile
2-5 nucleus lobes; can become hypersegmented in vitamin
B12 or folate deficiency
Phagocytic, but also has granules
Phagocytosed molecules/cells are exposed to respiratory
burst: NADPH oxidase produces superoxide, which is converted
to H2O2. H2O2 is then converted to OCl- byMPO.
Eosinophils contain bilobed nucleus. Intracellular granules stainwell with acid (e.g. eosin) dyes, hence "eosinophilic"
less
Granules contain cytotoxins: major basic protein, eosinophil
peroxidase, histaminase and arylsulfatase.
Defends against parasites: e.g., helminths eosinophilia is
a marker for some parasitic infections (note that protozoa and
noninvasive metazoa usually do not elicit eosinophilia)
Major basic protein is a toxic component of the lysosomal
granules and is an important mediator in the death of parasites
and protozoa.
Also upregulated in allergic reactions (esp. drug reactions)
and collagen vascular diseases (e.g. rheumatoid arthritis, Churg-
Strauss vasculitis)
Causes of eosinophilia can be remembered with
mnemonic: CCHINA
Connective tissue diseases
Cortisol deficiency
Helminthic infections
Idiopathic hypereosinophilic syndrome
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Neoplasia
Allergies
Monocytic &ineage nextOrgan Systems Hematology/Oncology Hematopoiesis
5 questions
Top of Form
339
Bottom of Form
Subclass of leukocytes; includes: monocytes and macrophagesMonocyte: Large, with a kidney-shaped nucleus
less
Following migration from bloodstream into tissues, they
differentiate into macrophages and dendritic cells
Macrophagesless
Phagocytose bacteria, cellular debris, damaged cells (e.g.
old RBCs), often via pseudopods Digested material in a phagosome is fused to a lysosome
phagolysosome
Antigen-presenting cells: during breakdown of foreign
material, MHC-II binds to antigens inside the macrophage
lysosomes, the complex translocates to the cell surface, and
theMHC-II presents antigens to CD4 receptors on T-cell surfaces
Plays a key role in atheroma formation
Epithelioid macrophages are the principal constituent of
granulomas
Dendritic cells are antigen-sampling and -presenting cells.less
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Express toll-like receptors, pattern recognition
receptors, MHC II, and Fc receptor
Induce naive T-cells, B-cells
&ymphocytes nextOrgan Systems Hematology/Oncology Hematopoiesis
7 questions
Top of Form
339
Bottom of Form
3 types: T cells, B cells/plasma cells, NK cells
T and B lymphocytes have small amounts of cytoplasm but a
round, dense nucleus
T cellsless
Mature in the thymus and differentiate into cytotoxic,
helper, and suppressor T cells
Major component of cellular immunity; comprise 80% ofcirculating lymphocytes
Cytotoxic T-cells express CD8 receptors; these interact
with MHC-I molecules that present antigen fragments to the CD8
receptors. Cytotoxic T-cells destroy infected cells and tumor cells
Helper T-cells express CD4 receptors; these interact
with MHC II molecules on antigen presenting cells
Helper T-cells secrete cytokines, activate B cells, and serve
as memory cells for future exposures to the same antigen
Suppressor T-cells are responsible for
immunologic tolerance they prevent T-cells from attacking the
body
B cells
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less
Produced in bone marrow
Mediate humoral immunity via antibody production
Activated by APCs but can also recognize antigens
independently. Maximal antibody production requires
immunological synapse with an activated helper T cell.
Differentiate into plasma cells and memory B cells
)loo$ ,ro'ps nextOrgan Systems Hematology/Oncology Hematopoiesis
4 questions
Top of Form
339
Bottom of Form
A & B oppose each other:less
A antigen B antibody
B antigen A antibody
Type A blood group: risk for gastric adenocarcinoma
A & B are codominantless
AB blood type: both A & B antigens noblood group
antibodies "universal recipient"
i is recessive. Thus Blood types A, B and O:
- Type A: Ai or AA- Type B: Bi or BB
- Type AB: AB only
- Type O: ii only
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O blood type: neither A nor B antigens both A and B antibodiesless
"Universal donor" because the RBCs arent immunogenic
(no surface ABO antigens)
Both A & B antibodies can only receive O blood type
Rh is another antigen found on RBC surfacesless
People who are Rh- do not develop antibodies against Rh
antigen until they are exposed (as during delivery of an
Rh+baby)
Example: Rh-mother exposed to Rh+fetal blood (via
placenta) will develop IgGanti-Rh antibodies Subsequentpregnancies where fetus is Rh+ hemolytic
disease of the newborn (aka erythroblastosis fetalis)
Fetus develops hepatosplenomegaly with ascites, and
cardiac hypertrophy from hypoxia
ABO incompatibility is actually protectiveagainst Rh
incompatibility. This is because when fetal cells are detected by
the maternal anti-A or anti-B IgM antibodies, complement is
activated and the RBC is lysed before sensitization to Rh antigencan occur.
)loo$ Composition nextOrgan Systems Hematology/Oncology Hematopoiesis
7 questions
Top of Form339
Bottom of Form
Blood contains plasma, platelets, leukocytes, and red blood
cells.
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Plasma: Fluid portion of blood, contains proteins.less
Albumin: maintains oncotic pressure of the blood.
Clinical Correlate: Burn victims and patients with
nephrotic syndrome lose albumin (through their skin and urine,
respectively), resulting in edema due to loss of oncotic pressure.
Gamma and beta globulins: transport hormones, metal
ions, and lipids.
Blood coagulation proteins, including fibrinogen fibrin is
the reaction that forms the fibrin clot.
Plasma without fibrinogen is serum.
Platelets: Degranulate to form blood clots.Leukocytes: White blood cells, include:
less
Neutrophils
Eosinophils
Basophils
Monocytes
Natural killer cells
T lymphocytes
B lymphocytes and plasma cells
Red blood cells:less
Hematocrit: Percent blood volume occupied by RBCs.
Normal = 45%.
In a centrifuged blood sample, plasma is the top
layer, leukocytes and platelets are in the middle layer,and RBCs are in the bottom layer.
Myeloi$ Tiss'e nextOrgan Systems Hematology/Oncology Hematopoiesis
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5 questions
Top of Form
339
Bottom of Form
Myeloid tissue (bone marrow)is the main site of
hematopoiesis.less
Bone marrow cell types:
- Stromal (1%)
- Myeloid (granulocytes, 65%)
- Erythroid (20%)- Lymphoid (14%)
Present in:
- Vertebrae
- Sternum
- Ribs
- Skull
- Pelvis
- Proximal femur
Clinical Correlate: Bone marrow aspirates are taken from
the superior iliac crest, sternum, or upper end of the tibia.
The myeloid to erythroid ratio (M:E)is the ratio of myeloid
precursor cells (immature white blood cell) to erythrocyte
precursor cells (immature erythrocytes). Useful in diagnosis of
blood dyscrasias. Normal: 3:1 to 5:1.less
Clinical Correlate: After severe hemorrhage the body
should stimulate erythropoiesis to compensate for blood loss
the M:E ratio will be decreased.
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Clinical Correlate: In cases of aplastic anemia (bone
marrow failure), the bone marrow is unresponsive to EPO
inappropriately high M:E ratio.
Myeloid tissues also phagocytize aged and defective red blood
cells (as do the spleen and liver) and are the sites of B
lymphocyte formation.
!latelets nextOrgan Systems Hematology/Oncology Hematopoiesis
7 questions
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339
Bottom of Form
Platelets: Mediators of hemostasis.less
Not actual cells, but cell fragments of megakaryocytes.
Platelets bud off from megakaryocytes in the bone marrow
and enter the circulation. Life span: 9 " 10 days.
Express surface proteins that mediate platelet aggregation and
clot formation.less
Surface protein GpIbbinds to vWF on injured endothelial
tissue.
Surface protein GpIIb-IIIabinds to fibrinogen to cross-link
platelet plug.
Contain granules of pro-coagulant mediators. Degranulation
primary hemostasis.less
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Thrombosthenin: Contractile internal structure for clot
retraction.
Alpha-granulescontain: platelet factor 4, PDGF (platelet-
derived growth factor), factor V, vWF and fibrinogen.
Delta-granulescontain: serotonin, Ca2+, ADP.
For information on the mechanism of platelet degranulation
and plug formation, reviewPrimary Hemostasis.
For information on platelet dysfunction, review Platelet
Dysfunction
-)C Morphology nextOrgan Systems Hematology/Oncology Hematopoiesis
10 questions
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Poikilocytosis = abnormally shaped RBCs
less Occurs when RBCs are traumatized (DIC, TTP/HUS) or
have membrane abnormalities (spherocytes, elliptocytes, Burr
cells)
Anisocytosis = normal-shaped RBCs but with variation in
size
Spherocytes occur in hereditary spherocytosis
Elliptocytes occur in hereditary elliptocytosis (membrane defects)less
RBCs become elliptical (deform) when passing through
capillaries
Target cells: surface area-to-volume ratio due to
RBC volume and/or RBC membrane.
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less
Target cells are associated with:
- Thalassemia
- Iron deficiency anemia
- Structurally aberrant hemoglobin disease: HbS, HbC which
also characteristically have the HbC crystal
- Splenectomy
- Liver disease
- Hereditary LCAT (lecithin-cholesterol acyl transferase)
deficiency
HbC patients have mild hemolytic anemia
Sickle cells are found in sickle cell anemia.
HbS molecules aggregate and form long filamentous fibers that
cause sickling of the RBC.less
Hypoxemia, acidosis and dehydration are common
precipitants.
Bite cells are formed when the spleen removes a Heinz bodyfrom an RBC
less
Heinz bodies form in G6PD deficiency
Basophilic stippling: ribosomal aggregatesless
Classic for lead poisoning; also occurs in severe anemias:
megaloblastic anemia, thalassemia
Echinocyte (burr cell): Seen in pyruvate kinase deficiency andrenal insufficiency
Schistocyte ("helmet cell"): RBC fragment, seen in any hemolytic
anemia, formed in cases of mechanical trauma, can be an
intrinsic abnormality of erythrocytes
Acanthocytes: irregularly spaced projections
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less
Found in abetalipoproteinemia and severe liver disease
Teardrop cells (Dacrocytes): found in myelofibrosis (replacement
of bone marrow by fibrous tissue aka myelophthistic anemia) and
thalassemia major
Erythropoiesis nextOrgan Systems Hematology/Oncology Hematopoiesis
4 questions
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Erythropoiesis: Production of new red blood cells.less
Regulated by EPO (erythropoietin).
EPO is a glycoprotein secreted by interstitial fibroblasts in
the kidney.
Takes place in myeloid tissue (bone marrow).less
Clinical Correlate: The presence of precursor cells, which
normally reside in the bone marrow, in the peripheral blood is a
useful marker for disease states.
Reticulocyte count can be used to gauge the ability of the
marrow to respond to anemic states. It is particularly useful for
differentiating anemia caused by increased destruction ofRBCsfrom anemia caused by decreased production of
RBCs.
For example, in cases of hemolytic anemia, the bone marrow
responds by increasingRBC production, as such reticulocytes
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are released at a higher rate into the peripheral blood. Thus,
reticulocyte count is increasedin states of RBC destruction.
In contrast, in cases of decreased production, such as iron or
B12 deficiency or aplastic anemia, the marrow is not able to
adequately respond by releasing reticulocytes into the blood,
thus reticulocyte count will be decreased.
Maturation of erythrocytes.less
Proerythroblast: RBC precursor cell, extrudes nucleus and
nucleoli to become a reticulocyte.
Reticulocyte: Non-nucleated, red, hemoglobin-containingcytoplasm. The final stages of maturation to RBCs (extrusion of
mitochondia and polyribosomes occur in the peripheral blood)
"C .isseminate$ "ntravasc'lar
Coag'lation/ next
Organ Systems Hematology/Oncology Hemostasis5 questions
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DIC is a consumptive coagulopathycharacterized by
generation of fibrin clots consumption of clotting factors and
platelets hemorrhage and often death.
Note: DIC is NOTa primary disorder, rather It is
a complicationof several different disease processes. You must
always look for an underlying cause.
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Common precipitating conditions include:Mnemonic:
ATTOMS
-Acute pancreatitis
-Trauma
-Transfusion reaction
-Obstetric causes such as abruptio placentae and amniotic fluid
embolism
-Malignancy
-Sepsis
Microthrombi can cause mechanical trauma to circulating RBCs
schistocytes aka helmet cells
Consumption of all hemostatic components leads to:
-Microangiopathic hemolytic anemia
-Thrombocytopenia
- Bleeding time
- PT and PTT
-Because it is a consumptive coagulopathy, coagulation
factors (Factor V, Factor VIII)
less Fibrin split products (D-dimers) as the excessive clotting
activates fibrinolysis(plasmin)
In addition to consumption of coagulation proteins, plasminogen
is activated hemorrhage.less
Activated plasmin cleavage of fibrin, factors V and VIII.
This exacerbates the hemorrhagic diathesis caused by
consumption of the factors.
Coag'lation Tests nextOrgan Systems Hematology/Oncology Hemostasis
5 questions
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Prothrombin Time (PT) evaluates the extrinsic system:
Factors VII, X, V, II and Iless
The normal PT is between 10-12 seconds.
INR (International Normalized Ratio) is a standardized
value for PT that is often quoted when
following warfarintherapy. The normal value is set at 1.
An elevated INR indicates relative increasein anti-coagulation (i.e. INR = 2-3)
PT can be seen with warfarin therapy, or any process
affecting the synthesis or consumption of coagulation factors (i.e.
liver disease and DIC (Disseminated Intravascular Coagulation);
respectively).
PTT (Partial Thromboplastin Time) evaluates the intrinsic
system: Factors XII, XI, IX, VIII, X, V, II and I.less
The normal PTT is between 25-40 seconds.
PTT is used to follow heparin but not LMWH (i.e.
enoxaparin)therapy.
PTT is seen with factor deficiencies, DIC, vWD and anti-
phospholipid syndrome (associated with SLE).
!latelet ysf'nction nextOrgan Systems Hematology/Oncology Hemostasis
3 questions
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Qualitative defects: Platelet count, PT and PTT are normal.
BT.less
Bleeding is not due to lack of platelets, instead there is a
problem with platelet function. This can be caused by several
different defective surface proteins or COX inhibition, clopidogrel
Adhesion defects: vWD, Bernard-Soulier diseaseless
vWD (von Willebrands Disease): usually autosomal
dominant, however some types of vWD are autosomal recessive:
- Type 1: autosomal dominant; production of vWF; treat
with DDAVP (desmopressin, an ADH analog), which releases
vWF from Weibel-Palade bodies of endothelial cells
- Type 2: autosomal dominant; abnormal vWF multimers
- Type 3: autosomal recessive; severe vWF deficiency
Bernard-Soulier: glycoprotein Ibis absent (autosomal
recessive). Note that despite being characterized as
a qualitativeplatelet defect, BSS is associated
withthrombocytopenia and giant platelets in the blood.
Think St. Bernard(a giant dog) to remember the giant plateletsin
Bernard-Soulier.
Aggregation defects: Glanzmann thrombasthenia, COX inhibitors
less Glanzmann thrombasthenia: autosomal recessive GPIIb-
IIIa deficiency, so neighboring platelets cant form fibrinogen
bridges to each other.
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Note the similarity between the pathogenesis of Glanzmann
thrombasthenia and ITP.
COX (cyclooxygenase) inhibitors TXA2. Examples:
aspirin, celecoxib
Coag'lation Casca$e efects nextOrgan Systems Hematology/Oncology Hemostasis
6 questions
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Unlike defects of primary hemostasis, defects of secondary
hemostasis cause large vessel bleeding hemarthroses, large
ecchymoses
PT is caused by deficiency of fibrinogen (factor I) or II, V, VII,
X ("1752")
PTT is caused by deficiency of all factors exceptVII and XIII
Hemophilia A (Factor 8 deficiency)less
X-linkedrecessive with variable severity
PTT but allother labs are normal: normal bleeding time,
normal PT
Hemophilia B (Factor 9 deficiency)less
S/Sx are identical to Hemophilia A, including laboratory
results demonstrating isolated PTTprolongation. Like hemophilia
A, hemophilia B is also X-linked recessive.
Keys to differentiating bleeding disorders:
1.Coagulation cascade defects will have a history of hematoma,
hemarthrosis and bleeding at circumcision
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Labs: PTT, normal BT. Normal PTis often found
in hemophiliabut PT prolongation can occur with factor II, V
or VII deficiency.
2.Platelet defects: patients will have history of mucosal
bleedingwith recurrent epistaxis, petechiae and small
ecchymoses and purpura
Labs: BT, PTT (in vWD because
of VIII deficiency), normal PT.
Also look at the platelet count as it will tell you if the
problem is due to platelet number or platelet function.
3.Bleeding caused by Vit K dependent factor deficiency, liver
disease, coumadin therapy PT, PTT, normal BT
Vitamin K deficiencyless
"1972": Factors 10, 9, 7, 2
Both PT and PTT are
Neonates: breast milk is vit K deficient and GI tract isnt
colonized yet with vit K-producing bacteria hemorrhagic
disease of the newborn
Cirrhotics: all coagulation factors except vWF are
synthesized in the liver. Factor VIII is synthesized in sinusoidal
endothelial cells and Kupffer cells of the liver as well as tubular
epithelial cells in the kidney. Recent research shows that FVIII is
actually increasedin cirrhosis.
Remember: vWF is made in endothelial cells and
megakaryocytes, and stored in platelets and endothelial cells.
When it is released complexes with VIII.
#ere$itary Thrombophilia
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nextOrgan Systems Hematology/Oncology Hemostasis
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Hypercoagulability is also known as thrombophilia.less
There are hereditary (primary) and acquired (secondary)
causes of thrombophilia.
Inherited causes become especially apparent in patientswho have a few acquired risk factors as well (prolonged
immobilization, endothelial damage, etc).
The most common cause or hereditary thrombophilia is
the Factor V Leiden mutation.less
The Leiden mutation is a single NT mutation in the Factor V
gene which causes Arg Gln substitution.
The mutant form of Factor V is resistant tocleavageby protein C.
Heterozygotes have a 5x higher risk of venous thrombosis
compared to 50x higher risk seen in homozygotes.
Another common cause of hereditary thrombophilia is a
mutant prothrombingene.less
The mutation is in the 3-UTR and leads to increased
expression of prothrombin and therefore increased risk of
venous thrombosis.
Elevated homocysteine levels can lead to venous and arterial
thrombosis.less
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The most common mutation causing
hyperhomocysteinemia is in the
enzyme MTHFR(methylenetetrahydrofolate reductase) but it can
also be due to inherited cystathione - synthetase deficiency.
Rarer causes of inherited thrombophilia includes:less
Protein C/S deficiency
Antithrombin III deficiency
von 0illebran$%s isease nextOrgan Systems Hematology/Oncology Hemostasis
4 questions
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Most commonly inherited as autosomal dominant
A combined primary and secondary hemostatic defect,
involving von Willebrand factor (vWF), which:less
1) vWF is made chiefly in endothelial cellsand to some
extent also in megakaryocytes.
a) The vWF that is synthesized in megakaryocytesis stored
in - granulesinside the platelets.
b) The vWF synthesized in endothelial cellsis storedin Weibel-Palade bodies.
Mediates platelet adhesion between subendothelial
collagen and platelet receptor GpIb
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In the blood, vWF binds to and stabilizes factor VIII
half-life of factor VIII.
Therefore, vWF deficiency causes both platelet
adhesion (prolonged bleeding time) and functional
efficiencyof Factor VIII (PTT is prolonged). PT/INR times are
normal.
vWD generally presents with mucosal type bleeding (similar to
other platelet defects) as well as menorrhagia. It
does NOTpresent with hematoma and hemarthrosis that is
typical of the hemophilias.Treatment of vWD generally consists of ddAVP (Desmopressin,
a Vasopressin analog) which causes release of vWF from
endothelial cells. Note this would not work in the subtype of vWD
which completely lacks vWF.
#enoch(Schonlein !'rp'ra next
Organ Systems Hematology/Oncology Hemostasis1 question
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A small vessel vasculitis that commonly affects the skin, GI tract,
kidneys and joints.
Also characterized by IgA-anti-IgA immune complex deposition.
Generally follows a viral respiratory infection.
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Clinical symptoms:
-Hematuria, proteinuria (renal sxs)
-Abdominal pain (GI sxs)
-Palpable purpura (skin sxs)
-Arthralgia (joint sxs)
Thrombocytopenia nextOrgan Systems Hematology/Oncology Hemostasis
22 questions
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Three basic causes of thrombocytopenia:less
1. platelet production:characterized by decreased
megakaryocytesin the bone marrow.
For example:
- Aplastic anemia- Alcohol
- Antineoplastic drugs
- Malignancy (e.g., myelofibrosis; metastatic spread of cancer to
bone marrow)
2. platelet destruction: peripheral destruction
associated with increased megakaryocytesin bone marrow.
For example:
- Bernard-Soulier syndrome- DIC (disseminated intravascular coagulation)
- Drug-induced thrombocytopenia (i.e., heparin, penicillin,
quinidine, methyldopa)
- HUS (hemolytic uremic syndrome) / TTP (thrombotic
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thrombocytopenic purpura)
- ITP (idiopathic / immunologic thrombocytopenic purpura)
3. platelet sequestration: platelets are retained in the
spleen.
For example: portal HTN hypersplenism
Clinical features are much different than coagulation defects!
Petechiae (small pinpoint hemorrhages) and purpura (small
ecchymoses) are common. Bleeding typically occurs from
mucosal surfaces (i.e. epistaxis, menorrhagia, bleeding gums),
GI bleeds.Laboratory investigation should take place when a bleeding
disorder is suspected.
Platelet count are decreased (< 150,000/mm3) in cases of
platelet destruction. bleeding time, while PT & PTT are
unchanged.
ITP (Idiopathic thrombocytopenic purpura): autoimmune
conditionless
Caused by auto-antibody against receptor GpIIbIIIa on the
platelet surface
In children, usually follows a viral infection and is self-
limited (vs. chronic course in adults)
Antiplatelet antibodies coat platelets which are then
removed by splenic macrophages
Look for thrombocytopenia with megakaryocytesin
the absenceof splenomegaly (to rule out splenic sequestration)
Clinical features: petechiae, menorrhagia
Dx: platelet count, bleeding time, megakaryocytes
in the bone marrow.
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TTP (Thrombotic thrombocytopenic purpura)less
Rare, life-threatening emergency characterized by
a classical pentadof symptoms:
1) Microangiopathic hemolytic anemia produces schistocytes
2) Thrombocytopenia
3) Renal failure (generally look for an BUN:Cr ratio)
4) CNS changes (i.e. mental status)
5) Fever
High Yield Fact: TTP/HUS are differentiated
from DIC by normalPT and PTT.
Due to a deficiency in the vWF multimer cleaving
protease ADAMTS-13. This deficiency can be acquired (e.g.
auto-antibodies against ADAMTS-13)
The deficient/defective protease larger multimers of vWF
persist. These have a higher propensity for aggregating and
forming whitemicrothrombi in the vasculature
White microthrombi in microvasculature organdysfunction, notably neurologic (stroke-like sx or altered mental
status) and renal failure (hematuria and BUN:Cr)
The thrombi also shear RBCs, causing a microangiopathic
hemolytic anemia schistocytesare present but not
pathognomonic
Tx: plasma exchange to remove auto-
antibodies; FFP transfusions
HUS (Hemolytic Uremic Syndrome)less
Most common cause of renal failure in children
Presents with classic triadof:
1) Thrombocytopenia
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2) Microangiopathic hemolytic anemia
3) Acute renal failure
Usually preceded by O157:H7 (Shiga-like toxin producing)
E. coli infection
Endothelial cells are damaged, predominantly in the kidney
platelets aggregate, forming microthrombi renal injury
uremia
Clot formation consumes platelets thrombocytopenia
Thrombi shear RBCs schistocytes, anemia
HIT (Heparin Induced Thrombocytopenia)less
Heparin binds to platelet antigen (Platelet Factor 4) Autoantibody formed against the Heparin/PF4 complex.
This is an example of Type II Hypersensitivity
These immune complexes induce activation of platelets
patients becomeprocoagulantand are at risk for
thromboembolic events
Note: the presence of heparin is required to trigger platelet
activation. Thus, all heparin administration should be
immediately stopped in patients suspected of having HIT
Ac1'ire$ Thrombophilia nextOrgan Systems Hematology/Oncology Hemostasis
7 questions
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Hypercoagulability is also known as thrombophilia.
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less
There are hereditary (primary) and acquired (secondary)
causes of thrombophilia.
Antiphospholipid antibody syndrome(also known as lupus
anticoagulant syndrome) is a commonly tested acquired
thrombophilia.less
In the blood stream, antibodies directly activate platelets
and complement hypercoagulable state.
Patients commonly present with a history of
recurrent DVT and miscarriages.
In vitro, the antibodies interfere with phospholipids (henceantiphospholipid) and inhibitcoagulation PTT.
Additionally, antiphospholipid antibodies can cause a false
positivefor syphilis.
Other causes of acquired thrombophilia include:less
Immobilization (bed rest, long plane flights)
Major surgery (especially orthopedic)
Oral contraceptive pills and pregnancy estrogendriven synthesis of coagulation factors
Malignancy tumor release of procoagulant mediators
Smoking (possibly endothelial damage, but true etiology is
unknown)
Obesity
Prosthetic valves
!rimary #emostasis nextOrgan Systems Hematology/Oncology Hemostasis
9 questions
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Platelet plug formation is primary hemostasis
Endothelial injury collagen exposed platelets adhere to vWFin the subendothelium (adhesion)
less
vWF (synthesized in megakaryocytes and endothelial cells)
binds GpIb on the platelet a dhesion
There is also a brief arteriolar vasoconstrictionmediated
by the local factorendothelin.
Binding of platelets also activates them to release their granules
which contain key molecules: ADP, Ca2+, and serotonin.
Thromboxane A2 (TXA A2) ia generated by the membrane
enzyme phospholipase A2.less
TXA2 activates more platelets ( aggregation)
ADP increases glycoprotein IIb/IIIas binding
of fibrinogen plug is strengthened
Serotonin enhances overall platelet procoagulability;mechanisms still being elucidated.
Role of ADP in platelet activation: ADP binds receptors on
platelet surface, causing insertion of GpIIb/IIIa (fibrinogen
receptor) allows aggregation of plateletsless
Antiplatelet agents ticlopidine and clopidogrel
block ADP receptors and thus inhibit expression of GpIIb/IIIa
Aggregationis mediated by fibrinogen, which binds GpIIb/IIIaon adjacent platelets
Aggregation is inhibited by endothelial cells that
release PGI2(prostacyclin) and NO
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Secon$ary #emostasis .Coag'lation
Casca$e/ nextOrgan Systems Hematology/Oncology Hemostasis
10 questions
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Goal: generate fibrin for the clotMany coagulation factors are secreted as zymogens. Upon
activation, they become serine proteasesthat can activate
downstream factors
Bradykinin, cleaved from HMWK (high molecular weight kinin),
vasodilates and increases vascular permeabilityless
It is short: 9 amino acids in length
Many reactions in the cascade require Ca2+and plateletphospholipid as cofactors
Factors X, IX, VII, II (mnemonic "1972") are vitamin K-dependentless
Their synthesis is inhibited by warfarin, a vitami